In the last several years, significant progress has been made in understanding the relevance of the T cell immune response to the clearance of the Gram-negative pathogen Salmonella typhimurium, a category B pathogen. We and others, have established that both CD4 and CDS T cells are essential to the protective immune response against infection with S. typhimurium, and these studies led to the identification of peptide epitopes recognized by bacteria-specific effector T cells. Also we have identified TCRgammadelta expressing iffiLs as a novel responding population following oral infection. In this proposal we plan to expand our studies to include an investigation into the role of cellular elements of the innate immune system (NK and NKT cells) in controlling the progression of Salmonella infection. We will focus our efforts on the following Aims: Aim 1. Do NK cells play a role in limiting the growth and/or accelerating the clearance of S. typhimurium following oral infection? Do NK cells influence the development of early innate response or a later adaptive T cell-mediated immune response to S. typhimurium? Aim 2. Do NKT cells play a role in limiting bacterial infection? Does this influence bacterial clearance and/or the development of a innate and/or adaptive immune response? The studies contained in this proposal are designed to address the contribution of lymphoid elements of the innate in the clearance of infection and the generation of protective immunity to a model Gram-negative pathogen Salmonella typhimurium. We hope to apply this in formation to the design of immune-modulating strategies that will evoke potent protective immunity as well as contribute to understanding the etiological link between infection with gram-negative pathogens in the development of autoimmune disease. Given that many of the cellular receptors in the mouse model have human counterparts, we argue that this murine model will yield valuable information that may be applied to the human setting.